Triiodothyronine (T3), inflammation and mortality risk in patients with acute myocardial infarction

Abstract

Objectives: To study the relationship between serum-free T3 (FT3), C-reactive protein (CRP) and all-cause mortality in patients with acute myocardial infarction (AMI).

Design: Prospective multicentre longitudinal cohort study.

Methods: Between December 2014 and December 2016, thyroid function and CRP were analysed in AMI (both ST-elevation (STEMI) and non-ST-elevation) patients from the Thyroxine in Acute Myocardial Infarction study. The relationship of FT3 and CRP at baseline with all-cause mortality up to June 2020 was assessed. Mediation analysis was performed to evaluate if CRP mediated the relationship between FT3 and mortality.

Results: In 1919 AMI patients (29.2% women, mean (s.d.) age: 64.2 (12.1) years and 48.7% STEMI) followed over a median (interquartile range) period of 51 (46-58) months, there were 277 (14.4%) deaths. Overall, lower serum FT3 and higher CRP levels were associated with higher risk of mortality. When divided the patients into tertiles based on the levels of FT3 and CRP; the group with the lowest FT3 and highest CRP levels had a 2.5-fold increase in mortality risk (adjusted hazard ratio (95% CI) of 2.48 (1.82-3.16)) compared to the group with the highest FT3 and lowest CRP values. CRP mediated 9.8% (95% CI: 6.1-15.0%) of the relationship between FT3 and mortality.

Conclusions: In AMI patients, lower serum FT3 levels on admission are associated with a higher mortality risk, which is partly mediated by inflammation. Adequately designed trials to explore the potential benefits of T3 in AMI patients are required.

Keywords: acute myocardial infarction; inflammation; mortality; triiodothyronine.

Figure 1

Cross-sectional association of baseline serum FT3 with CRP in all participants (A) and by baseline FT3 levels of ≤5.0 pmol/L (B) or >5.0 pmol/L (C). Association of CRP with FT3 levels at baseline using linear regression models with restricted cubic splines. The predicted means of CRP (blue line) with 95% CIs (grey area) were plotted against FT3, adjusted for age, sex, centre, ethnicity, BMI, smoking status, type of acute myocardial infarction (STEMI or NSTEMI), adjusted LVEF^*, ischemic heart disease, type 2 diabetes mellitus, hypertension, atrial fibrillation, hypothyroidism, serum creatinine and z-troponin. The relationship between CRP and the two FT3 subgroups (≤5.0 or >5.0 pmol/L) was linear but different; steeper unstandardised B coefficient in the ≤5.0 pmol/L group (−5.28 (−6.27 to −4.29), P  < 0.0001 than in the >5.0 pmol/L group (−1.61 (−2.64 to −0.58), P  < 0.002, respectively. CRP, C-reactive protein; FT3, free triiodothyronine; LT4, levothyroxine; LVEF, left ventricular ejection fraction; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction. ^*Adjusted for interval between the date of acute myocardial infarction and the date of echocardiogram.

Figure 2

Relationship of baseline serum FT3 with all-cause mortality in all participants (A) and those with FT3 ≤5.0 pmol/L (B) or >5.0 pmol/L (C). Prospective association of FT3 at baseline with risk of all-cause mortality using Cox proportional hazards model with restricted cubic splines. The predicted log-relative hazards (blue line) with 95% CIs (grey area) were plotted against baseline serum FT3 levels, adjusted for age, sex, centre, ethnicity, BMI, smoking status, type of acute myocardial infarction (STEMI or NSTEMI), adjusted LVEF^*, ischemic heart disease, type 2 diabetes mellitus, hypertension, atrial fibrillation, hypothyroidism, serum creatinine, z-troponin and CRP. When the data were analysed separately by baseline FT3 subgroups of ≤5.0 or >5.0 pmol/L, the negative linear relationship between baseline FT3 and all-cause mortality was only significant in the FT3 ≤5.0 pmol/L group with adjusted hazard ratio of 0.81 (0.72 to 0.92), P  < 0.0001. The hazard ratio in the FT3 >5.0 pmol/L group was non-significant (0.94 (0.73–1.20), P = 0.16). CRP, C-reactive protein; FT3, free triiodothyronine; LT4, levothyroxine; LVEF, left ventricular ejection fraction; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction. ^*Adjusted for interval between the date of acute myocardial infarction and the date of echocardiogram.

Figure 3

Sensitivity analysis for relationship between FT3 and all-cause mortality in various subgroups. Adjusted for age, sex, centre, ethnicity, BMI, smoking status, type of acute myocardial infarction (STEMI or NSTEMI), adjusted LVEF^*, ischemic heart disease, type 2 diabetes mellitus, hypertension, atrial fibrillation, hypothyroidism, serum creatinine, CRP and z-troponin, except those who were compared in each analysis. ^*Adjusted for interval between the date of acute myocardial infarction and the date of echocardiogram. The P for interaction was calculated by the addition of the interaction term (independent variable × FT3) to the fully adjusted model above.

Figure 4

T3 and CRP levels and risk of mortality. Adjusted for age, sex, centre, ethnicity, BMI, smoking status, type of acute myocardial infarction (STEMI or NSTEMI), adjusted LVEF^*, ischemic heart disease, type 2 diabetes mellitus, hypertension, atrial fibrillation, hypothyroidism, serum creatinine and z-troponin. The error bars represent the 95% CIs. FT3, free triiodothyronine; FT4, free thyroxine; hsCRP, high sensitivity C-reactive protein; LT4, levothyroxine; LVEF, left ventricular ejection fraction; STEMI, ST-elevation myocardial infarction; TSH, thyrotrophin. Definitions: high FT3>5.0 pmol/L, low CRP<1.0 mg/L, high CRP>6.0 mg/L, moderate CRP = 1.0–6.0 mg/L, moderate FT3 = 4.4–5.0 pmol/L, low FT3<4.4 pmol/L. ^*Adjusted for interval between the date of acute myocardial infarction and the date of echocardiogram.